Increased Levels of Plasma Tumor Necrosis Factor-α Mediate Schizophrenia Symptom Dimensions and Neurocognitive Impairments and Are Inversely Associated with Natural IgM and Paraoxonase 1 Activity

2019 ◽  
Author(s):  
Michael Maes ◽  
Sunee Sirivichayakul ◽  
Andressa Keiko Matsumoto ◽  
Annabel Maes ◽  
Ana Paula Michelin ◽  
...  
Keyword(s):  
Negative Symptoms ◽  
Cognitive Impairments ◽  
Word List ◽  
Psychomotor Retardation ◽  
Paraoxonase 1 ◽  
Necrosis Factor Alpha ◽  
Symptom Dimensions ◽  
Deficit Schizophrenia ◽  
Thought Disorders ◽  
Natural Igm

Accumulating evidence suggests that TNF-α-mediated immune-neurotoxicity contributes to cognitive impairments and the overall severity of schizophrenia (OSOS). There are no data whether peripheral IL-6 and IL-4 may affect the phenome of schizophrenia above and beyond the effects of TNF-α and whether those cytokines are regulated by lowered natural IgM to malondialdehyde (MDA) and paraoxonase 1 enzyme activity. We assessed the aforementioned biomarkers in schizophrenia patients with (n=40) and without (n=40) deficit schizophrenia and 40 healthy controls. Deficit schizophrenia was best predicted by a combination of increased IL-6 and PON1 status (QQ genotype and lowered CMPAase activity) and lowered IgM to MDA. Partial Least Squares bootstrapping shows that 41.0% of the variance in negative symptoms, psychosis, hostility, excitation, mannerism, psychomotor retardation, and formal thought disorders was explained by increased TNF-α and PON1 status (QQ genotype and lowered CMPAase activity), lowered IL-4 and IgM to MDA as well as male sex and lowered education. We found that 47.9% of the variance in verbal fluency, word list memory, true recall, Mini-Mental State Examination, and executive functions was predicted by increased TNF-α and lowered IL-4, IgM to MDA and education. In addition, both TNF-α and IL-4 levels were significantly associated with lowered IgM to MDA, while TNF-α was correlated with PON1 status. These data provide evidence that the symptomatic (both the deficit subtype and OSOS) and cognitive impairments in schizophrenia are to a large extent mediated by the effects of immune-mediated neurotoxicity as well as lowered regulation by the innate immune system.

Deficit schizophrenia and its features are associated with PON1 Q192R genotypes and lowered paraoxonase 1 (PON1) enzymatic activity: effects on bacterial translocation

CNS Spectrums ◽  
2020 ◽  
pp. 1-10 ◽  
Author(s):  
Andressa K. Matsumoto ◽  
Michael Maes ◽  
Thitiporn Supasitthumrong ◽  
Annabel Maes ◽  
Ana P. Michelin ◽  
...  
Keyword(s):  
Negative Symptoms ◽  
Immunoglobulin A ◽  
Quorum Quenching ◽  
Psychomotor Retardation ◽  
Paraoxonase 1 ◽  
Pon1 Activity ◽  
Phenyl Acetate ◽  
Gram Negative ◽  
Deficit Schizophrenia ◽  
Thought Disorders

Abstract Background. Primary deficit schizophrenia (DS) is characterized by enduring negative symptoms and represents a qualitatively different disease entity with respect to non-deficit schizophrenia (NDS). No studies investigated the association between the enzyme paraoxonase 1 (PON1) and DS and its phenomenology. Methods. In this case-control study, Thai women and men, aged 18 to 65 years, were divided in DS (n = 40) and NDS (n = 40) and were compared to controls (n = 40). PON1 activities against 4-(chloromethyl)phenyl acetate (CMPA) and phenylacetate were determined. Moreover, subjects were genotyped for their PON1 Q192R polymorphism and immunoglobulin A (IgA) levels responses directed to Gram-negative bacteria were measured. Results. DS is significantly associated with the QQ genotype and the Q allele as compared with NDS and controls. PON1 activities are significantly and inversely associated with negative symptoms, formal thought disorders, psychomotor retardation, excitation and DS. The presence of the Q allele is associated with increased IgA responses to Pseudomonas aeruginosa, Morganella morganii, and Pseudomonas putida as compared with RR carriers. Conclusions. The PON1 Q allele and lower PON1 activities especially against CMPA are associated with DS, indicating lowered quorum quenching abilities as well as lowered defenses against lipoperoxidation and immune activation. It is suggested that lowered PON1 activity in DS constitutes an impairment in the innate immune system which together with lowered natural IgM may cause lower immune regulation thereby predisposing toward greater neurotoxic effects of immune-inflammatory, oxidative and nitrosative pathways and Gram-negative microbiota.

scholarly journals In Schizophrenia, PON1 Q192R Genotypes and/or Lowered Paraoxonase 1 (PON1) Enzymatic Activity are Significantly Associated with the Deficit Syndrome, Negative Symptoms, Formal Thought Disorders, Psychomotor Retardation, Excitation and Increased IgA Levels to Gram-Negative Microbiota

2019 ◽  
Author(s):  
Andressa Keiko Matsumoto ◽  
Michael Maes ◽  
Annabel Maes ◽  
Ana Paula Michelin ◽  
Laura de Oliveira Semeão ◽  
...  
Keyword(s):  
Negative Symptoms ◽  
Quorum Quenching ◽  
Psychomotor Retardation ◽  
Paraoxonase 1 ◽  
Pon1 Activity ◽  
Phenyl Acetate ◽  
Gram Negative ◽  
Deficit Syndrome ◽  
Deficit Schizophrenia ◽  
Thought Disorders

Background: Primary deficit schizophrenia (DS) is characterized by enduring negative symptoms and represents a qualitatively different disease entity with respect to non-deficit schizophrenia (NDS). No studies investigated the association between the enzyme paraoxonase 1 (PON1) and DS and its phenomenology. Methods: In this case-control study, Thai women and men, aged 18-65 years, were divided in DS (n=40) and NDS (n=40) and were compared to controls (n=40). PON1 activities against 4-(chloromethyl)phenyl acetate (CMPA) and phenylacetate were determined. Moreover, subjects were genotyped for their PON1 Q192R polymorphism and IgA levels responses directed to Gram-negative bacteria were measured. Results: DS is significantly associated with the QQ genotype and the Q allele as compared with NDS and controls. PON1 activities are significantly and inversely associated with negative symptoms, formal thought disorders, psychomotor retardation, excitation and DS. The presence of the Q allele is associated with increased IgA responses to Pseudomonas aeruginosa, Morganella morganii, and Pseudomonas putida as compared with RR carriers. Conclusions: The PON1 Q allele and lower PON1 activities especially against CMPA are associated with DS, indicating lowered quorum quenching abilities as well as lowered defenses against lipoperoxidation and immune activation. It is suggested that lowered PON1 activity in DS constitutes an impairment in the innate immune system which together with lowered natural IgM may cause lower immune regulation thereby predisposing towards greater neurotoxic effects of immune-inflammatory, oxidative and nitrosative pathways and Gram-negative microbiota.

scholarly journals Lowered Antioxidant Defenses and Increased Oxidative Toxicity Are Hallmarks of Deficit Schizophrenia: Neurocognitive and Symptom Correlates

2020 ◽  
Author(s):  
Michael Maes ◽  
Sunee Sirivichayakul ◽  
Andressa Keiko Matsumoto ◽  
Anna Paula Michelin ◽  
Laura de Oliveira Semeão ◽  
...  
Keyword(s):  
Negative Symptoms ◽  
Psychomotor Retardation ◽  
Antioxidant Defenses ◽  
Paraoxonase 1 ◽  
Pon1 Activity ◽  
Lipid Hydroperoxides ◽  
Sh Groups ◽  
Deficit Schizophrenia ◽  
Immune Biomarkers ◽  
Thought Disorders

Background: There is now evidence that schizophrenia and deficit schizophrenia are neuro-immune conditions and that oxidative stress toxicity (OSTOX) may play a pathophysiological role. Aims of the study: To compare OSTOX biomarkers and antioxidant (ANTIOX) defenses in deficit versus non-deficit schizophrenia. Methods: We examined lipid hydroperoxides (LOOH), malondialdehyde (MDA), advanced oxidation protein products (AOPP), sulfhydryl (-SH) groups, paraoxonase 1 (PON1) activity and PON1 Q192R genotypes, total radical-trapping antioxidant parameter (TRAP) as well as immune biomarkers in patients with deficit (n=40) and non-deficit (n=40) schizophrenia and healthy controls (n=40). Results: Deficit schizophrenia is characterized by significantly increased levels of AOPP and lowered -SH, and PON1 activity, while no changes in the OSTOX/ANTIOX biomarkers were found in non-deficit schizophrenia. An increased OSTOX/ANTIOX ratio was significantly associated with deficit versus non-deficit schizophrenia (Odds ratio=3.15, p<0.001). Partial least squares analysis showed that 47.6% of the variance in a latent vector extracted from psychosis, excitation, hostility, mannerism, negative symptoms, psychomotor retardation, formal thought disorders, and neurocognitive test scores was explained by LOOH+AOPP, PON1 genotype + activity, CCL11, tumor necrosis factor (TNF)-α, IgA responses to neurotoxic tryptophan catabolites (TRYCATs), whereas -SH groups and IgM responses to MDA showed indirect effects mediated by OSTOX and neuro-immune biomarkers. Discussion: Our findings indicate that with increasing overall severity of schizophrenia, neuro-immune and neuro-oxidative (especially protein oxidation indicating chlorinative stress) toxicities become more prominent and together with lowered antioxidant defenses and impairments in innate immunity-associated resilience against neurotoxic processes shape a distinct nosological entity, namely deficit schizophrenia.

Schizophrenia phenomenology revisited: positive and negative symptoms are strongly related reflective manifestations of an underlying single trait indicating overall severity of schizophrenia

CNS Spectrums ◽  
2020 ◽  
pp. 1-10 ◽  
Author(s):  
Abbas F. Almulla ◽  
Hussein K. Al-Hakeim ◽  
Michael Maes
Keyword(s):  
Convergent Validity ◽  
Negative Symptoms ◽  
Discriminant Validity ◽  
Psychomotor Retardation ◽  
Future Research ◽  
Stable Phase ◽  
Deficit Schizophrenia ◽  
Latent Vector ◽  
Thought Disorders ◽  
Positive And Negative Symptoms

Abstract Background. To examine whether negative symptoms, psychosis, hostility, excitation, and mannerism (PHEM symptoms), formal thought disorders (FTD) and psychomotor retardation (PMR) are interrelated phenomena in major neurocognitive psychosis (MNP) or deficit schizophrenia and whether those domains belong to an underlying latent vector reflecting general psychopathology. Methods. In this study, we recruited 120 patients with MNP or deficit schizophrenia and 54 healthy subjects and measured the above-mentioned symptom domains. Results. In MNP, there were significant associations between negative and PHEM symptoms, FTD and PMR. A single latent trait, which is essentially unidimensional, underlies these key domains of schizophrenia and MNP and additionally shows excellent internal consistency reliability, convergent validity, and predictive relevance. Confirmatory Tedrad Analysis indicates that this latent vector fits a reflective model. The lack of discriminant validity shows that positive (and PHEM or psychotic) and negative symptoms greatly overlap and probably measure the same latent construct. Soft independent modeling of class analogy (SIMCA) shows that MNP (diagnosis based on negative symptoms) is better modeled using PHEM symptoms, FTD, and PMR than negative symptoms. Conclusions. In stable phase MNP, which is a restricted sample of the schizophrenia population, negative and PHEM symptoms, FTD and PMR belong to one underlying latent vector reflecting overall severity of schizophrenia (OSOS). The bi-dimensional concept of “positive” and “negative” symptoms cannot be validated and, therefore, future research in stable phase schizophrenia should consider that the latent phenomenon OSOS as well as its reflective manifestations are the key factors of schizophrenia phenomenology.

scholarly journals The Endogenous Opioid System in Schizophrenia and Treatment Resistant Schizophrenia: Increased Plasma Endomorphin 2, and κ and μ Opioid Receptors Are Associated with Interleukin-6

Diagnostics ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 633 ◽  
Author(s):  
Shatha Rouf Moustafa ◽  
Khalid F. Al-Rawi ◽  
Drozdstoi Stoyanov ◽  
Arafat Hussein Al-Dujaili ◽  
Thitiporn Supasitthumrong ◽  
...  
Keyword(s):  
Negative Symptoms ◽  
Psychomotor Retardation ◽  
Opioid System ◽  
Response To Treatment ◽  
Treatment Resistant ◽  
Endogenous Opioid System ◽  
Endogenous Opioid ◽  
Symptom Dimensions ◽  
Neurocognitive Impairments ◽  
Thought Disorders

Background: activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS) plays a key role in schizophrenia (SCZ) and treatment resistant SCZ. There are only a few data on immune and endogenous opioid system (EOS) interactions in SCZ and treatment resistant SCZ. Methods: we examined serum β-endorphin, endomorphin-2 (EM2), mu-opioid (MOR) and kappa-opioid (KOR) receptors, and interleukin (IL)-6 and IL-10 in 60 non responders to treatment (NRTT), 55 partial RTT (PRTT) and 43 normal controls. Results: serum EM2, KOR, MOR, IL-6 and IL-10 were significantly increased in SCZ as compared with controls. β-endorphin, EM2, MOR and IL-6 were significantly higher in NRTT than in PRTT. There were significant correlations between IL-6, on the one hand, and β-endorphin, EM2, KOR, and MOR, on the other, while IL-10 was significantly correlated with MOR only. A large part of the variance in negative symptoms, psychosis, hostility, excitation, mannerism, psychomotor retardation and formal thought disorders was explained by the combined effects of EM2 and MOR with or without IL-6 while increased KOR was significantly associated with all symptom dimensions. Increased MOR, KOR, EM2 and IL-6 were also associated with neurocognitive impairments including in episodic, semantic and working memory and executive functions. Conclusion: the EOS contributes to SCZ symptomatology, neurocognitive impairments and a non-response to treatment. In SCZ, EOS peptides/receptors may exert CIRS functions, whereas increased KOR levels may contribute to the pathophysiology of SCZ and EM2 and KOR to a non-response to treatment.

scholarly journals In Schizophrenia, Increased Plasma Igm/Iga Responses to Gut Commensal Bacteria are Associated with Negative Symptoms, Neurocognitive Impairments and the Deficit Phenotype

2018 ◽  
Author(s):  
Michael Maes ◽  
Buranee Kanchanatawan ◽  
Sunee Sirivichayakul ◽  
Andre F. Carvalho
Keyword(s):  
Azelaic Acid ◽  
Negative Symptoms ◽  
Commensal Bacteria ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Deficit Syndrome ◽  
Igm Antibodies ◽  
Deficit Schizophrenia ◽  
Neurocognitive Impairments ◽  
Natural Igm

Increased gut permeability (leaky gut) with increased translocation of Gram-negative bacteria plays a role in the gut-brain axis through effects on systemic immune-inflammatory processes. Deficit schizophrenia is characterized by an immune-inflammatory response combined with a deficit in natural IgM antibodies to oxidative specific epitopes (OSEs), which are a first line defense against bacterial infections. This study measured plasma IgA/IgM responses to 5 Gram-negative bacteria in association with IgM responses to malondialdehyde (MDA) and azelaic acid in 80 schizophrenia patients (40 with the deficit syndrome and 40 without) and in 38 healthy controls.Deficit schizophrenia was characterized by significantly increased IgA responses to Hafnei alvei, Pseudomonas aeruginosa, Morganella morganii and Klebsiella pneumoniae as compared with non-deficit schizophrenia. The presence of deficit schizophrenia was highly predicted by increased IgA responses to Pseudomonas putida and IgM responses to all 5 Gram-negative bacteria and lowered natural IgM to MDA and azelaic acid with a bootstrap area under the ROC curve of 0.960 (2000 random curves). A large proportion of the variance (41.5%) in the PANSS negative score was explained by the regression on IgA responses to K. pneumoniae and IgM responses to the 5 enterobacteria coupled with lowered IgM antibodies to azelaic acid. There were significant associations between IgA levels to Gram-negative bacteria and Mini Mental State Examination, Boston naming test, Verbal Fluency and Word List Memory test scores.These findings provide further evidence that deficit schizophrenia is a distinct phenotype of schizophrenia, which is characterized by an increased impact of Gram-negative commensal bacteria coupled with a deficit in natural IgM, pointing to aberrations in B1 cells. It is concluded that increased bacterial translocation and deficits in the compensatory immune-regulatory system (CIRS) may drive negative symptoms and neurocognitive impairments, which are hallmarks of deficit schizophrenia.

scholarly journals How to Construct a Bottom-Up Nomothetic Network Model and Disclose Novel Nosological Classes by Integrating Risk Resilience and Adverse Outcome Pathways with the Phenome of Schizophrenia

2020 ◽  
Vol 10 (9) ◽  
pp. 645 ◽  
Author(s):  
Michael Maes ◽  
Aristo Vojdani ◽  
Piotr Galecki ◽  
Buranee Kanchanatawan
Keyword(s):  
Negative Symptoms ◽  
Adverse Outcome ◽  
Psychomotor Retardation ◽  
Oxidative Stress Biomarkers ◽  
Case Definitions ◽  
Current Case ◽  
Bottom Up ◽  
Thought Disorders ◽  
Using Data ◽  
Adverse Outcome Pathways

Current case definitions of schizophrenia (DSM-5, ICD), made through a consensus among experts, are not cross-validated and lack construct reliability validity. The aim of this paper is to explain how to use bottom-up pattern recognition approaches to construct a reliable and replicable nomothetic network reflecting the direct effects of risk resilience (RR) factors, and direct and mediated effects of both RR and adverse outcome pathways (AOPs) on the schizophrenia phenome. This study was conducted using data from 40 healthy controls and 80 patients with schizophrenia. Using partial least squares (PLS) analysis, we found that 39.7% of the variance in the phenomenome (lowered self-reported quality of life) was explained by the unified effects of AOPs (IgA to tryptophan catabolites, LPS, and the paracellular pathway, cytokines, and oxidative stress biomarkers), the cognitome (memory and executive deficits), and symptomatome (negative symptoms, psychosis, hostility, excitation, mannerism, psychomotor retardation, formal thought disorders); 55.8% of the variance in the symptomatome was explained by a single trait extracted from AOPs and the cognitome; and 22.0% of the variance in the latter was explained by the RR (Q192R polymorphism and CMPAase activity, natural IgM, and IgM levels to zonulin). There were significant total effects (direct + mediated) of RR and AOPs on the symptomatome and the phenomenome. In the current study, we built a reliable nomothetic network that reflects the associations between RR, AOPs, and the phenome of schizophrenia and discovered new diagnostic subclasses of schizophrenia based on unified RR, AOPs, and phenome scores.

scholarly journals Chronic Fatigue and Fibromyalgia Symptoms are Key Components of Deficit Schizophrenia and are Strongly Associated with Activated Immune-Inflammatory Pathways

2019 ◽  
Author(s):  
Abbas Almulla ◽  
Hussein Al-Hakeim ◽  
Mokhlad Abed ◽  
André Carvalho ◽  
Michael Maes
Keyword(s):  
Convergent Validity ◽  
Rating Scale ◽  
Somatic Symptoms ◽  
Internal Consistency Reliability ◽  
Chronic Fatigue ◽  
Psychomotor Retardation ◽  
Deficit Schizophrenia ◽  
Thought Disorders ◽  
Symptom Domains

A subset of patients with schizophrenia experience physio-somatic symptoms reminiscent of chronic fatigue and fibromyalgia. In schizophrenia, these symptoms contribute to impaired quality of life, and are strongly related to neuro-cognitive deficits, and increased IgA responses to tryptophan catabolites. Negative and PHEM (psychosis, hostility, excitation, mannerism) symptoms, psychomotor retardation (PMR) and formal thought disorders, appear to be manifestations of a single trait reflecting overall severity of schizophrenia (OSOS). In this study, 120 patients with deficit schizophrenia (DEFSCZ) and 54 healthy subjects were assessed with the FibroFatigue (FF) rating scale, and the above-mentioned symptom domains as well as neuro-cognitive tests and biomarkers were measured. In DEFSCZ, there were robust associations between the FF score and all above-mentioned symptom domains, and impairments in semantic and episodic memory and executive functions. Furthermore, the FF score loaded highly on an OSOS latent vector (LV), which showed adequate convergent validity, internal consistency reliability and predictive relevance and fitted a reflective model. Soft Independent Modelling of Class Analogy (SIMCA) showed that the FF items discriminated DEFSCZ from controls with an overall accuracy of 100%. Interleukin IL-1β, IL-1 receptor antagonist (sIL-1RA), tumour necrosis factor (TNF)-α and CCL-11 (eotaxin) explained 66.8% of the variance in the FF score and 59.4% of the variance in OSOS. In conclusion, these data show that physio-somatic symptoms are a core component of the phenomenology of DEFSCZ and are largely mediated by neurotoxic effects of activated immune pathways, including aberrations in CCL-11, IL-1β and TNF-α signalling.

scholarly journals How to Construct a Bottom-up Nomothetic Network Model and Disclose Novel Nosological Classes by Integrating Risk Resilience and Adverse Outcome Pathways with the Phenome of Schizophrenia

2020 ◽  
Author(s):  
Michael Maes ◽  
Aristo Vodjani ◽  
Piotr Galecki ◽  
Buranee Kanchanatawan
Keyword(s):  
Negative Symptoms ◽  
Adverse Outcome ◽  
Psychomotor Retardation ◽  
Oxidative Stress Biomarkers ◽  
Case Definitions ◽  
Current Case ◽  
Bottom Up ◽  
Thought Disorders ◽  
Using Data ◽  
Adverse Outcome Pathways

Current case definitions of schizophrenia (DSM-5, ICD), made through a consensus among experts, are not cross-validated and lack construct reliability validity. The aim of this paper is to explain how to use bottom-up pattern recognition approaches to construct a reliable and replicable nomothetic network reflecting the direct effects of risk resilience (RR) factors, and direct and mediated effects of both RR and adverse outcome pathways (AOPs) on the schizophrenia phenome. This study was conducted using data of 40 healthy controls and 80 patients with schizophrenia. Using partial least Squares (PLS) analysis, we found that 39.7% of the variance in the phenomenome (lowered self-reported quality of life) was explained by the unified effects of AOPs (IgA to tryptophan catabolites, LPS, and the paracellular pathway, cytokines, and oxidative stress biomarkers), the cognitome (memory and executive deficits), and symptomatome (negative symptoms, psychosis, hostility, excitation, mannerism, psychomotor retardation, formal thought disorders); 55.8% of the variance in the symptomatome was explained by a single trait extracted from AOPs and the cognitome; and 22.0% of the variance in the latter was explained by the RR (Q192R polymorphism and CMPAaase activity, natural IgM, and IgM levels to zonulin). There were significant total effects (direct + mediated) of RR and AOPs on the symptomatome and phenomenome. In the current study, we built a reliable nomothetic network that reflects the associations between RR, AOPs, and the phenome of schizophrenia and discovered new diagnostic subclasses of schizophrenia based on unified RR, AOPs, and phenome scores.

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